I. The Impact of Arterial Aging on the heart, brain, and health outcomes New protocol is being finalized to introduce new measurements of arterial impedance that would provide an important insight into the effect of arterial aging on the up- and downstream organs. In the same direction, analysis of arterial stiffness. To elaborate on our, and others', previous findings of a strong role of arterial stiffness parameter, namely PWV, as a predictor of morbidity and mortality, we analyzed data of normotensive and untreated hypertensive community-dwelling subjects showing an early contribution of arterial wave reflection on myocardial diastolic dysfunction before the progression of hypertension (Canepa, AlGhatrif, et al., 2013). We have examined the prevalence and correlates of subaortic septal thickening and found that it increase with age without any effect on exercise capacity. Projects aimed at examining the longitudinal impact of wave reflection on myocardial function and structure are in process. At the other end, data from the BLSA have shown that individuals in the upper quintile of carotid intimal medial thickness, another age-associated trait, or bilateral carotid plaque were at greatest risk for dementia. These findings underscore the possibility that early intervention to retard arterial aging may help delay or prevent onset of dementia and AD (Wendell et al., 2012). We have also found that PWV is associated with increased inter-arm blood pressure difference, an independent risk factor for mortality (Canepa, Milaneschi, et al., 2013). II. A. Patterns and Determinants of the Longitudinal Changes in Arterial stiffness Analysis of the longitudinal data from the Baltimore Longitudinal Study on Aging (BLSA) revealed a non-linear, longitudinal increase in pulse wave velocity (PWV) with aging that is more pronounced in men (AlGhatrif et al., 2013). Analysis of longitudinal data from SardiNIA project showed similar results, but in addition it showed an interesting separation between the longitudinal trajectories of PWV and SBP in men with advancing age; this suggests that other age-related process, such as aortic dilatation, might blunt the effect of wall stiffening and cause the separation of PWV and SBP; this paper is currently in press in Hypertension. To test the hypothesis that aortic dilatation contributes to the separation between PWV and SBP in men, preliminary analysis of data from BLSA confirmed the separation between SBP and PWV in older men, and showed greater rates of longitudinal aortic dilatation among men, which supports our hypothesis; these results were presented as an oral presentation during the at the American Heart Association Scientific Sessions, 2013, Dallas, TX. To examine earlier manifestation of arterial stiffness with aging, we analyzed data on carotid diameter from the SardiNIA project, we found earlier decline in distensibility between the age of 30 to 50 is a result of impaired recoil rather than restricted expansion; these results were presented as an oral presentation during the American College of Cardiology meeting 2014, Washington D.C. To examine the underlying causes of the more pronounced aortic dilatation in older men, we performed an analysis of data from Taiwan project; interestingly, we have observed that the magnitude of pressure wave reflection was associated with larger aortic diameter in men but not in women, which might contribute to the greater aortic dilatation in men with aging; this manuscript is in preparation for submission and the abstract was presented as an oral presentation at the North American Artery Society meeting, 2013. These interesting findings support our working hypothesis of major role of age-associated process that is independent from other traditional cardiovascular risk factors. B. Genetic and Environmental Underpinnings of Accelerated Cardiovascular Aging -Genetic determinates: Earlier results from the SardiNIA study have revealed a potential role of the Col4A1 gene (Tarasov 2009) and a second genetic element located in a desert region of the genome (Mitchell 2012), findings which have been confirmed in replication studies and larger Consortia-based analysis. Work is in progress to examine genetic determinants of the longitudinal change in PWV. -Environmental determinants: Except for blood pressure, we have previously found a minimal role of traditional cardiovascular risk factors in the progression of arterial stiffness(AlGhatrif et al., 2013). We have also found that central obesity might introduce bias to PWV measurements (Canepa et al. 2014). In addition, we have found that vitamin D modulates the association of circulating insulin-like growth factor-1 with carotid artery intima-media thickness (Ameri et al. 2014). We have also found that bone mineral density plays a role in the inverse relationship between body size and aortic calcification (Canepa et 2014). Projects examining the role of low-grade inflammation in arterial stiffness using data from the BLSA and the SardiNIA projects are in progress. As far as cardiac funciton, Results from the BLSA have shown that visceral, rather than subcutaneous fat, is associated with worse myocardial diastolic dysfunction (M Canepa, Strait, et al., 2013. In addition, the VALIDATE study, which will assess the factors leading to unhealthy vascular aging as measured by PWV, intimal medial thickness, coronary calcium scoring, among other tests, is currently in final stages of completing the follow-up visit. Another project has been started aiming to assess age-associated changes in regional adiposity and novel cardiovascular risk factors such as coronary endothelial function and myocardial triglyceride content using magnetic resonance imaging. C. Interventions to Retard Arterial Aging Resveratrol, a natural compound in grapes and red wine with antioxidant and anti-inflammatory properties, has been associated with improved health and prolonged lifespan in mice. There is evidence that acute and chronic use of resveratrol is associated with improved endothelial dysfunction. A Phase 1 and 2 double-blind randomized study is in progress aiming to examine the effect of resveratrol on PWV in 90 overweight /obese subjects beyond the age of 50.